Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study

Journal of Hepatology

Volumn 65, Issue 3, 2016, Pages 490-498

  Bogomolov, Pavel ^a,b   Alexandrov, Alexander ^c   Voronkova, Natalia ^a,b   Macievich, Maria ^a,b   Kokina, Ksenia ^a,b   Petrachenkova, Maria ^a,b   Lehr, Thorsten ^d   Lempp, Florian A ^e,f   Wedemeyer, Heiner ^g   Haag, Mathias ^h,i,j   Schwab, Matthias ^h,i,j   Haefeli, Walter E ^e,f   Blank, Antje ^e,f   Urban, Stephan ^e,f  

^a M F VLADIMIRSKY MOSCOW REGIONAL RESEARCH CLINICAL INSTITUTE   (Russian Federation)

^b Centrosoyuz Clinical Hospital   (Russian Federation)

^c Myr GmbH   (Germany)

^d SAARLAND UNIVERSITY   (Germany)

^e Heidelberg   (Germany)

^f UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^g HANNOVER MEDICAL SCHOOL   (Germany)

^h DR MARGARETE FISCHER BOSCH INSTITUTE OF CLINICAL PHARMACOLOGY   (Germany)

ⁱ UNIVERSITY OF TÜBINGEN   (Germany)

^j UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

more..

Author keywords

Chronic hepatitis B; Entry inhibitor; Hepatitis B treatment; Hepatitis B virus receptor; Hepatitis D; Hepatitis D treatment; Myrcludex B; SLC10A1); Sodium taurocholate co transporting polypeptide (NTCP; Virus kinetic modeling

Indexed keywords

ALANINE AMINOTRANSFERASE; ANTIVIRUS AGENT; ASPARTATE AMINOTRANSFERASE; BILE ACID; GAMMA GLUTAMYLTRANSFERASE; HEPATITIS B SURFACE ANTIGEN; MYRCLUDEX B; PEGINTERFERON ALPHA2A; UNCLASSIFIED DRUG; VIRUS RNA; LIPOPEPTIDE; MYRCLUDEX-B;

ADULT; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CHRONIC HEPATITIS; CLINICAL ARTICLE; DELTA AGENT HEPATITIS; DRUG ERUPTION; DRUG RESPONSE; DRUG TOLERABILITY; EOSINOPHILIA; FEMALE; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; HUMAN; LIVER CIRRHOSIS; LYMPHOCYTOPENIA; MALE; MONOTHERAPY; NEUTROPENIA; NEUTROPHIL COUNT; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); THROMBOCYTE COUNT; THROMBOCYTOPENIA; TREATMENT DURATION; CLINICAL TRIAL; CONTROLLED STUDY; HEPATITIS B; HEPATITIS B VIRUS; HEPATITIS DELTA VIRUS; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL;

HEPATITIS B; HEPATITIS B VIRUS; HEPATITIS D; HEPATITIS DELTA VIRUS; HUMANS; LIPOPEPTIDES;

EID: 84979663414     PISSN: 01688278     EISSN: 16000641     Source Type: Journal    
DOI: 10.1016/j.jhep.2016.04.016     Document Type: Article

References (54)

1. [1] Taylor, J.M., Virology of hepatitis D virus. Semin Liver Dis 32 (2012), 195–200.
2. [2] Alvarado-Mora, M.V., Locarnini, S., Rizzetto, M., Pinho, J.R., An update on HDV: virology, pathogenesis and treatment. Antivir Ther 18 (2013), 541–548.
3. [3] Noureddin, M., Gish, R., Hepatitis delta: epidemiology, diagnosis and management 36 years after discovery. Curr Gastroenterol Rep, 16, 2014, 365.
4. [4] Wedemeyer, H., Hepatitis D revival. Liver Int 31 (2011), 140–144.
5. [5] Rizzetto, M., Hepatitis, D., Virus: introduction and epidemiology. Cold Spring Harb Perspect Med, 5, 2015.
6. [6] Rizzetto, M., Current management of delta hepatitis. Liver Int 33 (2013), 195–197.
7. [7] Goyal, A., Murray, J.M., The impact of vaccination and antiviral therapy on hepatitis B and hepatitis D epidemiology. PLoS One, 9, 2014, e110143.
8. [8] Heidrich, B., Manns, M.P., Wedemeyer, H., Treatment options for hepatitis delta virus infection. Curr Infect Dis Rep 15 (2013), 31–38.
9. [9] Triantos, C., Kalafateli, M., Nikolopoulou, V., Burroughs, A., Meta-analysis: antiviral treatment for hepatitis D. Aliment Pharmacol Ther 35 (2012), 663–673.
10. [10] Wedemeyer, H., Yurdaydin, C., Dalekos, G.N., Erhardt, A., Cakaloglu, Y., Degertekin, H., et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 364 (2011), 322–331.
11. [11] Heidrich, B., Yurdaydin, C., Kabacam, G., Ratsch, B.A., Zachou, K., Bremer, B., et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology 60 (2014), 87–97.
12. [12] Gunsar, F., Akarca, U.S., Ersoz, G., Kobak, A.C., Karasu, Z., Yuce, G., et al. Two-year interferon therapy with or without ribavirin in chronic delta hepatitis. Antivir Ther 10 (2005), 721–726.
13. [13] Niro, G.A., Ciancio, A., Gaeta, G.B., Smedile, A., Marrone, A., Olivero, A., et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology 44 (2006), 713–720.
14. [14] Rizzetto, M., Smedile, A., Pegylated interferon therapy of chronic hepatitis D: in need of revision. Hepatology 61 (2015), 1109–1111.
15. [15] Lamers, M.H., Kirgiz, O.O., Heidrich, B., Wedemeyer, H., Drenth, J.P., Interferon-alpha for patients with chronic hepatitis delta: a systematic review of randomized clinical trials. Antivir Ther 17 (2012), 1029–1037.
16. [16] Niro, G.A., Ciancio, A., Tillman, H.L., Lagget, M., Olivero, A., Perri, F., et al. Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Aliment Pharmacol Ther 22 (2005), 227–232.
17. [17] Soriano, V., Vispo, E., Sierra-Enguita, R., Mendoza, C., Fernandez-Montero, J.V., Labarga, P., et al. Efficacy of prolonged tenofovir therapy on hepatitis delta in HIV-infected patients. Aids 28 (2014), 2389–2394.
18. [18] Soriano, V., Barreiro, P., de Mendoza, C., Tenofovir for hepatitis delta. Hepatology 63 (2016), 1395–1396.
19. [19] Rizzetto, M., Ciancio, A., The prenylation inhibitor, lonafarnib: a new therapeutic strategy against hepatitis delta. Lancet Infect Dis 15 (2015), 1119–1120.
20. [20] Yust-Katz, S., Liu, D., Yuan, Y., Liu, V., Kang, S., Groves, M., et al. Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma. Cancer 119 (2013), 2747–2753.
21. [21] Koh, C., Canini, L., Dahari, H., Zhao, X., Uprichard, S.L., Haynes-Williams, V., et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis 15 (2015), 1167–1174.
22. [22] Poutay, D., Sabra, M., Abou Jaoudé, G., Chemin, I., Trepo, C., Vaillant, A., et al. Nucleic acid polymers are efficient in blocking hepatitis delta virus entry in vitro. The Global Viral Hepatitis Summit. 2015, German Liver Foundation, Berlin.
23. [23] Replicor homepage; 2015 [cited 2015 23.11.2015]; Available from: http://replicor.com/.
24. [24] Lamas Longarela, O., Schmidt, T.T., Schoneweis, K., Romeo, R., Wedemeyer, H., Urban, S., et al. Proteoglycans act as cellular hepatitis delta virus attachment receptors. PLoS One, 8, 2013, e58340.
25. [25] Yan, H., Zhong, G., Xu, G., He, W., Jing, Z., Gao, Z., et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. elife, 1, 2012, e00049.
26. [26] Petersen, J., Dandri, M., Mier, W., Lutgehetmann, M., Volz, T., von Weizsacker, F., et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 26 (2008), 335–341.
27. [27] Urban, S., Bartenschlager, R., Kubitz, R., Zoulim, F., Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 147 (2014), 48–64.
28. [28] Vercauteren, K., Brown, R.J., Mesalam, A.A., Doerrbecker, J., Bhuju, S., Geffers, R., et al. Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice. Gut, 2015.
29. [29] Schulze, A., Analyse der frühen Schritte der Hepatitis B Virus Infektion: Zell-Polarisierung, Differenzierung und Zell-assoziierte Heparansulfat-Proteoglykane als essentielle Faktoren für die Etablierung einer Hepatitis B Virus Infektion. 2008, Heidelberg University.
30. [30] Schulze, A., Schieck, A., Ni, Y., Mier, W., Urban, S., Fine mapping of pre-S sequence requirements for hepatitis B virus large envelope protein-mediated receptor interaction. J Virol 84 (2009), 1989–2000.
31. [31] Volz, T., Allweiss, L., Barek, M.B., Warlich, M., Lohse, A.W., Pollok, J.M., et al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol 58 (2013), 861–867.
32. [32] Dandri, M., Lutgehetmann, M., Mouse models of hepatitis B and delta virus infection. J Immunol Methods 410 (2014), 39–49.
33. [33] Lutgehetmann, M., Mancke, L.V., Volz, T., Helbig, M., Allweiss, L., Bornscheuer, T., et al. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology 55 (2012), 685–694.
34. [34] Schieck, A., Schulze, A., Gahler, C., Muller, T., Haberkorn, U., Alexandrov, A., et al. Hepatitis B virus hepatotropism is mediated by specific receptor recognition in the liver and not restricted to susceptible hosts. Hepatology 58 (2013), 43–53.
35. [35] Blank, A., Markert, C., Hohmann, N., Carls, A., Mikus, G., Lehr, T., et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor Myrcludex B. J Hepatol 65 (2016), 483–489.
36. [36] Schulze, A., HBV/HDV infection inhibition study using a human derived liver cell culture. OMZ study report 201. 2010, Otto Meyerhof Zentrum, Heidelberg.
37. [37] Mederacke, I., Bremer, B., Heidrich, B., Kirschner, J., Deterding, K., Bock, T., et al. Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics. J Clin Microbiol 48 (2010), 2022–2029.
38. [38] Neumann, A.U., Lam, N.P., Dahari, H., Gretch, D.R., Wiley, T.E., Layden, T.J., et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282 (1998), 103–107.
39. [39] Canini, L., Perelson, A.S., Viral kinetic modeling: state of the art. J Pharmacokinet Pharmacodyn 41 (2014), 431–443.
40. [40] Colombatto, P., Civitano, L., Oliveri, F., Coco, B., Ciccorossi, P., Flichman, D., et al. Sustained response to interferon-ribavirin combination therapy predicted by a model of hepatitis C virus dynamics using both HCV RNA and alanine aminotransferase. Antivir Ther 8 (2003), 519–530.
41. [41] Snoeck, E., Chanu, P., Lavielle, M., Jacqmin, P., Jonsson, E.N., Jorga, K., et al. A comprehensive hepatitis C viral kinetic model explaining cure. Clin Pharmacol Ther 87 (2010), 706–713.
42. [42] Haag, M., Hofmann, U., Murdter, T.E., Heinkele, G., Leuthold, P., Blank, A., et al. Quantitative bile acid profiling by liquid chromatography quadrupole time-of-flight mass spectrometry: monitoring hepatitis B therapy by a novel Na-taurocholate cotransporting polypeptide inhibitor. Anal Bioanal Chem 407 (2015), 6815–6825.
43. [43] Keskin, O., Wedemeyer, H., Tüzün, A., Zachou, K., Deda, X., Dalekos, G.N., et al. Association between level of hepatitis D virus RNA at week 24 of pegylated interferon therapy and outcome. Clin Gastroenterol Hepatol 13 (2015), 2342–2349 e1-2.
44. [44] Wedemeyer, H., Re-emerging interest in hepatitis delta: new insights into the dynamic interplay between HBV and HDV. J Hepatol 52 (2010), 627–629.
45. [45] Guedj, J., Rotman, Y., Cotler, S.J., Koh, C., Schmid, P., Albrecht, J., et al. Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling. Hepatology 60 (2014), 1902–1910.
46. [46] Glebe, D., Urban, S., Knoop, E.V., Cag, N., Krass, P., Grun, S., et al. Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes. Gastroenterology 129 (2005), 234–245.
47. [47] Wooddell CI, Chavez D, Goetzmann JE, Guerra B, Peterson RM, Lee H, et al. Reductions in cccDNA under NUC and ARC-520 therapy in chimpanzees with chronic hepatitis B virus infection implicate integrated DNA in maintaining circulating HBsAg (ID32). In: Diseases AAftSoL, editor. The AASLD Liver Meeting; 2015; San Francisco: Hepatology; 2015.
48. [48] Op den Brouw, M.L., Binda, R.S., van Roosmalen, M.H., Protzer, U., Janssen, H.L., van der Molen, R.G., et al. Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus. Immunology 126 (2009), 280–289.
49. [49] Shi, B., Ren, G., Hu, Y., Wang, S., Zhang, Z., Yuan, Z., HBsAg inhibits IFN-alpha production in plasmacytoid dendritic cells through TNF-alpha and IL-10 induction in monocytes. PLoS One, 7, 2012, e44900.
50. [50] Glebe, D., Aliakbari, M., Krass, P., Knoop, E.V., Valerius, K.P., Gerlich, W.H., Pre-s1 antigen-dependent infection of Tupaia hepatocyte cultures with human hepatitis B virus. J Virol 77 (2003), 9511–9521.
51. [51] Pizarro, J.C., Vulliez-le Normand, B., Riottot, M.M., Budkowska, A., Bentley, G.A., Structural and functional characterization of a monoclonal antibody specific for the preS1 region of hepatitis B virus. FEBS Lett 509 (2001), 463–468.
52. [52] Vaz, F.M., Paulusma, C.C., Huidekoper, H., de Ru, M., Lim, C., Koster, J., et al. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology 61 (2015), 260–267.
53. [53] Khurana, S., Raufman, J.P., Pallone, T.L., Bile acids regulate cardiovascular function. Clin Transl Sci 4 (2011), 210–218.
54. [54] Rainer, P.P., Primessnig, U., Harenkamp, S., Doleschal, B., Wallner, M., Fauler, G., et al. Bile acids induce arrhythmias in human atrial myocardium–implications for altered serum bile acid composition in patients with atrial fibrillation. Heart 99 (2013), 1685–1692.